Measurement of apolipoprotein E and amyloid β clearance rates in the mouse brain using bolus stable isotope labeling
Open accessAbstract
Background: Abnormal proteostasis due to alterations in protein turnover has been postulated to play a central role in several neurodegenerative diseases. Therefore, the development of techniques to quantify protein turnover in the brain is critical for understanding the pathogenic mechanisms of these diseases. We have developed a bolus stable isotope-labeling kinetics (SILK) technique coupled with multiple reaction monitoring mass spectrometry to measure the clearance of proteins in the mouse brain. Results: Cohorts of mice were pulse labeled with 13 C 6-leucine and the brains were isolated after pre-determined time points. The extent of label incorporation was measured over time using mass spectrometry to measure the ratio of labeled to unlabeled apolipoprotein E (apoE) and amyloid β (Aβ). The fractional clearance rate (FCR) was then calculated by analyzing the time course of disappearance for the labeled protein species. To validate the technique, apoE clearance was measured in mice that overexpress the low-density lipoprotein receptor (LDLR). The FCR in these mice was 2.7-fold faster than wild-type mice. To demonstrate the potential of this technique for understanding the pathogenesis of neurodegenerative disease, we applied our SILK technique to determine the effect of ATP binding cassette A1 (ABCA1) on both apoE and Aβ clearance. ABCA1 had previously been shown to regulate both the amount of apoE in the brain, along with the extent of Aβ deposition, and represents a potential molecular target for lowering brain amyloid levels in Alzheimer's disease patients. The FCR of apoE was increased by 1.9- and 1.5-fold in mice that either lacked or overexpressed ABCA1, respectively. However, ABCA1 had no effect on the FCR of Aβ, suggesting that ABCA1 does not regulate Aβ metabolism in the brain. Conclusions: Our SILK strategy represents a straightforward, cost-effective, and efficient method to measure the clearance of proteins in the mouse brain. We expect that this technique will be applicable to the study of protein dynamics in the pathogenesis of several neurodegenerative diseases, and could aid in the evaluation of novel therapeutic agents.
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Written from the paper’s full text.
TL;DR
The paper develops a bolus 13C6-leucine stable isotope-labeling kinetics (SILK) method with LC-MS/MS to measure fractional clearance rates (FCRs) of apoE and Aβ in mouse brain cortex. It validates the method by showing faster apoE clearance in LDLR-overexpressing mice and finds that ABCA1 levels alter apoE clearance but not Aβ clearance.
Key findings
- In LDLR transgenic mice, apoE FCR was 0.25 ± 0.019 pools/hr versus 0.093 ± 0.011 pools/hr in wild-type controls, a 2.7-fold faster clearance; apoE pool size was 44.7 ± 1.9 ng/mg versus 125.4 ± 9.1 ng/mg, respectively.
- ABCA1 deletion increased apoE FCR from 0.09 ± 0.015 to 0.17 ± 0.010 pools/hr (1.9-fold, p < 0.0001), and ABCA1 overexpression increased apoE FCR from 0.10 ± 0.019 to 0.15 ± 0.022 pools/hr (1.5-fold, p = 0.106; only the ABCA1−/− difference was significant).
- ABCA1 levels did not alter Aβ clearance: Aβ FCR was 0.238 ± 0.016 pools/hr in Wt controls versus 0.247 ± 0.016 in ABCA1 Tg (p = 0.69), and 0.247 ± 0.023 in Wt controls versus 0.243 ± 0.016 in ABCA1−/− (p = 0.88); Aβ half-life was approximately 2.8–2.9 hr.
- Wild-type apoE FCR was reproducible across three cohorts: 0.093, 0.10, and 0.09 pools/hr, mean 0.094 ± 0.003 pools/hr.
Methods
- Mice were intraperitoneally pulse-labeled with 13C6-leucine at 200 mg/kg body weight; cortex was collected at predetermined time points, and apoE or Aβ was immunoprecipitated, trypsin-digested, and analyzed by UPLC/MS/MS with multiple reaction monitoring.
- MRM assays used apoE peptide LQAEIFQAR and Aβ peptide LVFFAEDVGSNK; labeled/unlabeled peptide ratios were converted to tracer-to-tracee ratios using cell-derived apoE and Aβ standard curves (apoE standard curve slope 0.976, R² = 0.9954).
- FCR was calculated as the negative slope of the natural log of TTR over time under steady-state conditions; n = 5–6 mice per time point, and experiments used 3.5-month-old mice before detectable plaque deposition.
Limitations
- The paper states that experiments were performed in young animals prior to plaque deposition and that it cannot rule out the possibility that changes in Aβ clearance develop as mice age.
- The paper notes that only cortex was used, though the technique could be applied to other brain regions.
- Evident from the text: the ABCA1 Tg apoE FCR increase was not statistically significant despite the reported 1.5-fold change, and wild-type cohorts differed in apoE pool size, which the authors attribute to different genetic backgrounds.
Model-written summary. Check it against the paper before relying on it.
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Cites
Statistics
Claims the paper makes
23 of 40 cited sources checked · 17 supported · 0 flagged · accuracy not yet measured
- Premisecitation
Astrocytes are the main cell type in the brain that produce apoE.
“Since astrocytes are the main cell type in the brain that produce apoE [20], we used primary astrocyte cultures to produce a labeled apoE standard curve.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [20] Kim J, Basak JM, Holtzman DM: The role of apolipoprotein E in Alzheimer’s disease. Neuron. 2009, 63: 287-303. 10.1016/j.neuron.2009.06.026. source
- Study design and conductcitation
Standard curves for both apoE and Aβ were developed using the SILAC method to accurately compare TTR values between individual brain samples and across cohorts of animals.
“In order to accurately compare the TTR values between individual brain samples and across cohorts of animals, we developed standard curves for both apoE and Aβ using the stable isotope labeling of amino acids in cell culture (SILAC) method [35].”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [35] Ong SE, Blagoev B, Kratchmarova I, Kristensen DB, Steen H, Pandey A, Mann M: Stable isotope labeling by amino acids in cell culture, SILAC, as a simple and accurate approach to expression proteomics. Mol Cell Proteomics. 2002, 1: 376-386. 10.1074/mcp.M200025-MCP200. source
- Rests on an assumption: The standard curve generated from astrocyte-secreted apoE is representative of brain apoE labeling.
- Premisecitation
LDLR transgenic mice that overexpress LDLR in the brain have significantly decreased levels of brain apoE.
“Previously we have shown that LDLR transgenic mice that overexpress LDLR in the brain have significantly decreased levels of brain apoE [27].”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [27] Kim J, Castellano JM, Jiang H, Basak JM, Parsadanian M, Pham V, Mason SM, Paul SM, Holtzman DM: Overexpression of low-density lipoprotein receptor in the brain markedly inhibits amyloid deposition and increases extracellular A beta clearance. Neuron. 2009, 64: 632-644. 10.1016/j.neuron.2009.11.013. source
- Premisecitation
The half-life of Aβ clearance in previous studies ranged from 30 min to 2 h.
“The half-life of Aβ clearance in these studies ranged from 30 min to 2 h.”
Quote in the paperNot a substantial claim2 of 4 sources checked- cites [48] Savage MJ, Trusko SP, Howland DS, Pinsker LR, Mistretta S, Reaume AG, Greenberg BD, Siman R, Scott RW: Turnover of amyloid beta-protein in mouse brain and acute reduction of its level by phorbol ester. J Neurosci. 1998, 18: 1743-1752. source
The Discussion (page not provided) estimates an Aβ turnover half-life of 1.0–2.5 hours in gene-targeted mouse brain, supporting the claim that clearance occurs on an hours-long timescale. It does not support the stated range of 30 minutes to 2 hours: its lower bound is longer and its upper bound is longer. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [49] Cirrito JR, May PC, O’Dell MA, Taylor JW, Parsadanian M, Cramer JW, Audia JE, Nissen JS, Bales KR, Paul SM, et al: In vivo assessment of brain interstitial fluid with microdialysis reveals plaque-associated changes in amyloid-beta metabolism and half-life. J Neurosci. 2003, 23: 8844-8853. source
The Results section ('Half-life of Aβ in the brain interstitial fluid'; page unavailable) reports an ISF Aβ half-life of 1.97 hours in young mice, supporting the 2-hour figure. It does not report a 30-minute half-life; it also reports 3.78 hours in aged mice, so the stated range does not describe this paper's findings. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [50] Barten DM, Guss VL, Corsa JA, Loo A, Hansel SB, Zheng M, Munoz B, Srinivasan K, Wang B, Robertson BJ, et al: Dynamics of {beta}-amyloid reductions in brain, cerebrospinal fluid, and plasma of {beta}-amyloid precursor protein transgenic mice treated with a {gamma}-secretase inhibitor. J Pharmacol Exp Ther. 2005, 312: 635-643. source
- cites [51] Abramowski D, Wiederhold KH, Furrer U, Jaton AL, Neuenschwander A, Runser MJ, Danner S, Reichwald J, Ammaturo D, Staab D, et al: Dynamics of Abeta turnover and deposition in different beta-amyloid precursor protein transgenic mouse models following gamma-secretase inhibition. J Pharmacol Exp Ther. 2008, 327: 411-424. 10.1124/jpet.108.140327. source
- Findingown data
There is no statistical difference in the production rate of apoE between wild-type and LDLR transgenic mice.
“no statistical difference in the PR was observed between Wt and LDLR Tg mice.”
Quote in the paperSubstantial claim- Rests on an assumption: The disappearance of 13C6-leucine-labeled apoE and Aβ from the brain follows a monoexponential decay, so the negative slope of the log-transformed labeled/unlabeled ratio over time equals the fractional clearance rate.
- Rests on an assumption: The immunoprecipitation and MRM assays measure only the intended apoE and Aβ peptides, without interference from other proteins or peptides.
- Findingown data
The fractional clearance rate (FCR) of apolipoprotein E (apoE) in LDLR transgenic mice is 2.7-fold faster than in wild-type mice.
“The FCR in these mice was 2.7-fold faster than wild-type mice.”
- Also stated in: § LDLR overexpression enhances the apoE clearance rate · plain
“The FCR of apoE was 2.7-fold faster in the LDLR Tg mice in comparison to the Wt mice”
Quote in the paperSubstantial claim- Rests on an assumption: The disappearance of 13C6-leucine-labeled apoE and Aβ from the brain follows a monoexponential decay, so the negative slope of the log-transformed labeled/unlabeled ratio over time equals the fractional clearance rate.
- Rests on an assumption: The immunoprecipitation and MRM assays measure only the intended apoE and Aβ peptides, without interference from other proteins or peptides.
- Also stated in: § LDLR overexpression enhances the apoE clearance rate · plain
- Findingown data
The apoE pool size is 2.8-fold higher in wild-type mice than in LDLR transgenic mice.
“while the apoE pool size was 2.8-fold higher for the Wt mice in comparison to the LDLR Tg mice.”
Quote in the paperNot a substantial claim- Rests on an assumption: The disappearance of 13C6-leucine-labeled apoE and Aβ from the brain follows a monoexponential decay, so the negative slope of the log-transformed labeled/unlabeled ratio over time equals the fractional clearance rate.
- Rests on an assumption: The immunoprecipitation and MRM assays measure only the intended apoE and Aβ peptides, without interference from other proteins or peptides.
- Findingnone given
The bolus stable isotope-labeling kinetics (SILK) technique coupled with multiple reaction monitoring mass spectrometry can measure the clearance of proteins in the mouse brain.
“We have developed a bolus stable isotope-labeling kinetics (SILK) technique coupled with multiple reaction monitoring mass spectrometry to measure the clearance of proteins in the mouse brain.”
Quote in the paperSubstantial claim- Rests on an assumption: The disappearance of 13C6-leucine-labeled apoE and Aβ from the brain follows a monoexponential decay, so the negative slope of the log-transformed labeled/unlabeled ratio over time equals the fractional clearance rate.
- Rests on an assumption: The immunoprecipitation and MRM assays measure only the intended apoE and Aβ peptides, without interference from other proteins or peptides.
- Findingown data
ABCA1 levels (overexpression or deletion) do not alter the fractional clearance rate of amyloid β (Aβ) in the mouse brain.
“For Aβ, no differences were observed in the FCR, PS, or PR values (Table 3).”
Quote in the paperSubstantial claim- Rests on an assumption: The disappearance of 13C6-leucine-labeled apoE and Aβ from the brain follows a monoexponential decay, so the negative slope of the log-transformed labeled/unlabeled ratio over time equals the fractional clearance rate.
- Rests on an assumption: The immunoprecipitation and MRM assays measure only the intended apoE and Aβ peptides, without interference from other proteins or peptides.
- Rests on an assumption: The FCR of total Aβ reflects the clearance of the relevant Aβ species in the brain.
- Findingown data
ABCA1 levels (overexpression or deletion) do not alter the production rate of Aβ in the mouse brain.
“For Aβ, no differences were observed in the FCR, PS, or PR values (Table 3).”
Quote in the paperSubstantial claim- Rests on an assumption: The disappearance of 13C6-leucine-labeled apoE and Aβ from the brain follows a monoexponential decay, so the negative slope of the log-transformed labeled/unlabeled ratio over time equals the fractional clearance rate.
- Rests on an assumption: The immunoprecipitation and MRM assays measure only the intended apoE and Aβ peptides, without interference from other proteins or peptides.
- Rests on an assumption: The FCR of total Aβ reflects the clearance of the relevant Aβ species in the brain.
- Findingown data
The apoE pool size is decreased by 51% in ABCA1−/− mice compared to wild-type mice.
“The apoE PS decreased by 20% in ABCA1 Tg mice and by 51% in ABCA1−/− mice compared to Wt mice.”
Quote in the paperSubstantial claim- Rests on an assumption: The disappearance of 13C6-leucine-labeled apoE and Aβ from the brain follows a monoexponential decay, so the negative slope of the log-transformed labeled/unlabeled ratio over time equals the fractional clearance rate.
- Rests on an assumption: The immunoprecipitation and MRM assays measure only the intended apoE and Aβ peptides, without interference from other proteins or peptides.
- Findingown data
Following bolus injection, there is a rapid increase in the amount of 13C6-leucine in the plasma of mice over the first hour.
“Following the injection, we observed a rapid increase in the amount of 13 C6-leucine in the plasma of the mice over the first hour, as measured by the ratio of labeled to unlabeled free leucine quantified by GC-MS (Figure 1B).”
Quote in the paperNot a substantial claim - Findingown data
ABCA1 overexpression and deletion increase the fractional clearance rate of apoE from the brain.
“These results demonstrate that both ABCA1 overexpression and deletion increase the fractional clearance rate of apoE from the brain”
Quote in the paperSubstantial claim- Rests on an assumption: The antibodies used for immunoprecipitation and ELISA specifically and quantitatively measure apoE and Aβ.
- Findingown data
There are no differences in the production rate of apoE among ABCA1 transgenic, ABCA1−/−, and wild-type mice.
“No differences were observed in the PR of apoE.”
Quote in the paperSubstantial claim- Rests on an assumption: The disappearance of 13C6-leucine-labeled apoE and Aβ from the brain follows a monoexponential decay, so the negative slope of the log-transformed labeled/unlabeled ratio over time equals the fractional clearance rate.
- Rests on an assumption: The immunoprecipitation and MRM assays measure only the intended apoE and Aβ peptides, without interference from other proteins or peptides.
- Findingown data
The apoE pool size is decreased by 20% in ABCA1 transgenic mice compared to wild-type mice.
“The apoE PS decreased by 20% in ABCA1 Tg mice and by 51% in ABCA1−/− mice compared to Wt mice.”
Quote in the paperNot a substantial claim- Rests on an assumption: The disappearance of 13C6-leucine-labeled apoE and Aβ from the brain follows a monoexponential decay, so the negative slope of the log-transformed labeled/unlabeled ratio over time equals the fractional clearance rate.
- Rests on an assumption: The immunoprecipitation and MRM assays measure only the intended apoE and Aβ peptides, without interference from other proteins or peptides.
- Findingown data
The labeling of three different cohorts of wild-type control mice resulted in similar FCR values for apoE (0.093, 0.10, and 0.09 pools/hr, mean = 0.094 pools/h ± 0.003).
“the labeling of three different cohorts of wild-type (Wt) control mice resulted in similar FCR values for apoE (Table 2; 0.093, 0.10, and 0.09 pools/hr, mean = 0.094 pools/h ± 0.003).”
Quote in the paperSubstantial claim- Rests on an assumption: The disappearance of 13C6-leucine-labeled apoE and Aβ from the brain follows a monoexponential decay, so the negative slope of the log-transformed labeled/unlabeled ratio over time equals the fractional clearance rate.
- Rests on an assumption: The immunoprecipitation and MRM assays measure only the intended apoE and Aβ peptides, without interference from other proteins or peptides.
- Findingnone given
The stable isotope quickly appears in both plasma and brain within minutes of the injection.
“Since the stable isotope quickly appears in both plasma and brain within minutes of the injection”
Quote in the paperNot a substantial claim - Findingown data
We observed a half-life for Aβ of approximately 2.8-2.9 h.
“Consistent with these studies, we observed a half-life for Aβ of approximately 2.8-2.9 h (Table 3).”
Quote in the paperSubstantial claim- Rests on an assumption: The antibodies used for immunoprecipitation and ELISA specifically and quantitatively measure apoE and Aβ.
- Interpretationown data
Different brain apoE levels are not caused by variations in apoE catabolism.
“Since we observed similar FCR values from the Wt mice across the different genetic strains, our results suggest that the different brain apoE levels are not caused by variations in apoE catabolism.”
Quote in the paperSubstantial claim- Rests on an assumption: The disappearance of 13C6-leucine-labeled apoE and Aβ from the brain follows a monoexponential decay, so the negative slope of the log-transformed labeled/unlabeled ratio over time equals the fractional clearance rate.
- Rests on an assumption: The immunoprecipitation and MRM assays measure only the intended apoE and Aβ peptides, without interference from other proteins or peptides.
- Interpretationown data
ABCA1 does not regulate Aβ metabolism in the brain.
“However, ABCA1 had no effect on the FCR of Aβ, suggesting that ABCA1 does not regulate Aβ metabolism in the brain.”
Quote in the paperSubstantial claim- Rests on an assumption: The disappearance of 13C6-leucine-labeled apoE and Aβ from the brain follows a monoexponential decay, so the negative slope of the log-transformed labeled/unlabeled ratio over time equals the fractional clearance rate.
- Rests on an assumption: The immunoprecipitation and MRM assays measure only the intended apoE and Aβ peptides, without interference from other proteins or peptides.
- Rests on an assumption: The FCR of total Aβ reflects the clearance of the relevant Aβ species in the brain.
- Interpretationown data
ABCA1 acts via another pathway, such as directly influencing Aβ aggregation, to regulate amyloid deposition.
“suggesting ABCA1 acts via another pathway, such as directly influencing Aβ aggregation, to regulate amyloid deposition.”
Quote in the paperSubstantial claim - Interpretationreasoning
ABCA1 likely alters Aβ levels through a mechanism distinct from modulating apoE levels.
“Because of the opposing effects of ABCA1 deletion and overexpression on Aβ accumulation, ABCA1 likely alters Aβ levels through a mechanism distinct from modulating apoE levels.”
Quote in the paperSubstantial claim - Premisecitation
Lipidation of apoE significantly alters its propensity to bind to LDLR, with increased lipid levels leading to enhanced binding.
“The lipidation of apoE also significantly alters its propensity to bind to LDLR, with increased lipid levels leading to enhanced binding [46].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [46] Innerarity TL, Mahley RW: Enhanced binding by cultured human fibroblasts of apo-E-containing lipoproteins as compared with low density lipoproteins. Biochemistry. 1978, 17: 1440-1447. 10.1021/bi00601a013. source
- Interpretationreasoning
The faster apoE clearance rate in ABCA1 Tg mice may be due to increased LDLR-mediated clearance of the more highly lipidated apoE-containing lipoprotein particles.
“As a result, the faster apoE clearance rate in the ABCA1 Tg mice may be due to increased LDLR-mediated clearance of the more highly lipidated apoE-containing lipoprotein particles.”
Quote in the paperSubstantial claim - Study design and conductown data
The SILK technique yielded highly reproducible results through the use of cell-derived labeled protein standards.
“Through the use of cell-derived labeled protein standards, this technique yielded highly reproducible results.”
Quote in the paperNot a substantial claim - Interpretationown data
The effect of ABCA1 on Aβ deposition in the brain may not occur due to altered metabolism of Aβ.
“our current data suggests that the effect of ABCA1 on Aβ deposition in the brain may not occur due to altered metabolism of Aβ.”
Quote in the paperSubstantial claim- Rests on an assumption: The mice used in the Aβ clearance experiments were at a young age prior to the onset of plaque deposition.
- Interpretationown data
ABCA1 likely regulates Aβ deposition in the brain through a mechanism other than altering Aβ metabolism, such as through modulating the propensity of Aβ to aggregate.
“Consequently, ABCA1 likely regulates Aβ deposition in the brain through a mechanism other than altering Aβ metabolism, such as through modulating the propensity of Aβ to aggregate.”
Quote in the paperSubstantial claim- Rests on an assumption: The mice used in the Aβ clearance experiments were at a young age prior to the onset of plaque deposition.
- Interpretationreasoning
The SILK technique is particularly suitable for measuring the kinetics of proteins that turn over rapidly.
“this technique is particularly suitable for measuring the kinetics of proteins that turn over rapidly.”
Quote in the paperSubstantial claim - Premisecitation
A previous study measuring the disappearance of radiolabeled Aβ injected into the brains of ABCA1−/− mice found no effect on Aβ clearance across the blood-brain barrier.
“A previous study measuring the disappearance of radiolabeled Aβ injected into the brains of ABCA1−/− mice also found no effect on Aβ clearance across the blood–brain barrier [47].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [47] Akanuma S, Ohtsuki S, Doi Y, Tachikawa M, Ito S, Hori S, Asashima T, Hashimoto T, Yamada K, Ueda K, et al: ATP-binding cassette transporter A1 (ABCA1) deficiency does not attenuate the brain-to-blood efflux transport of human amyloid-beta peptide (1–40) at the blood–brain barrier. Neurochem Int. 2008, 52: 956-961. 10.1016/j.neuint.2007.12.002. source
- Interpretationown data
The effect of ABCA1 levels on the clearance of Aβ from the mouse brain was measured in vivo for the first time.
“the effect of ABCA1 levels on the clearance of Aβ from the mouse brain were measured in vivo for the first time.”
Quote in the paperSubstantial claim - Interpretationnone given
This labeling technique is particularly useful for comparing the kinetics of a protein in cohorts of mice with different genetic manipulations.
“We demonstrate that this labeling technique is particularly useful for comparing the kinetics of a protein in cohorts of mice with different genetic manipulations.”
Quote in the paperSubstantial claim - Interpretationnone given
The SILK technique can be used to measure the clearance of proteins from the mouse brain.
“In this study, we describe a stable isotope pulse labeling kinetics (SILK) technique that can be used to measure the clearance of proteins from the mouse brain.”
Quote in the paperSubstantial claim
- Classified as probably not a substantial claim. 15
- May combine two claims. 15
- The quote only partly states this claim. 1
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationABCA1 is a transmembrane protein that plays an important role in the efflux of cholesterol and phospholipids to lipid-poor apolipoproteins.
“ABCA1 is a transmembrane protein that plays an important role in the efflux of cholesterol and phospholipids to lipid-poor apolipoproteins [39].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [39] Lawn RM, Wade DP, Garvin MR, Wang X, Schwartz K, Porter JG, Seilhamer JJ, Vaughan AM, Oram JF: The Tangier disease gene product ABC1 controls the cellular apolipoprotein-mediated lipid removal pathway. J Clin Invest. 1999, 104: R25-R31. 10.1172/JCI8119. source
Classified as probably not a substantial claim.
PremisecitationIndependent of apoE isoform, the amount of apoE in the brain appears to be critical for determining the extent of amyloid deposition.
“Independent of apoE isoform, the amount of apoE in the brain appears to be critical for determining the extent of amyloid deposition [25,26].”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [25] Bales KR, Verina T, Dodel RC, Du Y, Altstiel L, Bender M, Hyslop P, Johnstone EM, Little SP, Cummins DJ, et al: Lack of apolipoprotein E dramatically reduces amyloid beta-peptide deposition. Nat Genet. 1997, 17: 263-264. 10.1038/ng1197-263. source
- cites [26] Kim J, Jiang H, Park S, Eltorai AE, Stewart FR, Yoon H, Basak JM, Finn MB, Holtzman DM: Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of amyloid-beta amyloidosis. J Neurosci. 2011, 31: 18007-18012. 10.1523/JNEUROSCI.3773-11.2011. source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationApoE4 is the strongest known genetic risk factor for late-onset Alzheimer's disease.
“ApoE4 is currently the strongest known genetic risk factor for late-onset AD, and as a result significant effort has been devoted to understanding apoE’s physiological function in the brain along with its role in AD pathogenesis [20].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [20] Kim J, Basak JM, Holtzman DM: The role of apolipoprotein E in Alzheimer’s disease. Neuron. 2009, 63: 287-303. 10.1016/j.neuron.2009.06.026. source
Classified as probably not a substantial claim.
PremisecitationIn the brain, the level of ABCA1 modulates the extent of apoE lipidation and apoE levels.
“In the brain, the level of ABCA1 has been shown to modulate the extent of apoE lipidation and apoE levels.”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [28] Wahrle SE, Jiang H, Parsadanian M, Legleiter J, Han X, Fryer JD, Kowalewski T, Holtzman DM: ABCA1 is required for normal central nervous system ApoE levels and for lipidation of astrocyte-secreted apoE. J Biol Chem. 2004, 279: 40987-40993. 10.1074/jbc.M407963200. source
- cites [29] Hirsch-Reinshagen V, Zhou S, Burgess BL, Bernier L, McIsaac SA, Chan JY, Tansley GH, Cohn JS, Hayden MR, Wellington CL: Deficiency of ABCA1 impairs apolipoprotein E metabolism in brain. J Biol Chem. 2004, 279: 41197-41207. 10.1074/jbc.M407962200. source
- cites [30] Wahrle SE, Jiang H, Parsadanian M, Kim J, Li A, Knoten A, Jain S, Hirsch-Reinshagen V, Wellington CL, Bales KR, et al: Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease. J Clin Invest. 2008, 118: 671-682. source
May combine two claims.
PremisecitationThe apoE-containing lipoprotein particles isolated from the CSF of ABCA1−/− mice are poorly lipidated, while those from the CSF of mice overexpressing ABCA1 have higher levels of lipidation compared to wild-type animals.
“However, the apoE containing lipoprotein particles isolated from the cerebral spinal fluid (CSF) of ABCA1−/− mice were poorly lipidated, while those from the CSF of mice overexpressing ABCA1 had higher levels of lipidation compared to Wt animals [28,30].”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [28] Wahrle SE, Jiang H, Parsadanian M, Legleiter J, Han X, Fryer JD, Kowalewski T, Holtzman DM: ABCA1 is required for normal central nervous system ApoE levels and for lipidation of astrocyte-secreted apoE. J Biol Chem. 2004, 279: 40987-40993. 10.1074/jbc.M407963200. source
- cites [30] Wahrle SE, Jiang H, Parsadanian M, Kim J, Li A, Knoten A, Jain S, Hirsch-Reinshagen V, Wellington CL, Bales KR, et al: Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease. J Clin Invest. 2008, 118: 671-682. source
The Introduction reports abnormally small apoE-containing particles in the CSF of ABCA1-deficient mice and describes their apoE as poorly lipidated. In “ApoE levels and solubility in PrP-mAbca1 Tg mice” (page unavailable), CSF particles from overexpressing mice only tended to be larger than controls, which the authors say suggests greater lipidation. The claim states that greater CSF lipidation as a definite finding; the paper’s direct lipidation measurement was instead of particles secreted by cultured astrocytes. (LLM, conf=0.85)
Experimental — accuracy not yet measured
Classified as probably not a substantial claim.
PremisecitationBoth overexpression and deletion of ABCA1 in the mouse brain result in a decrease in apoE protein level.
“Both the overexpression and deletion of ABCA1 in the mouse brain resulted in a decrease in apoE protein level [28-30].”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [28] Wahrle SE, Jiang H, Parsadanian M, Legleiter J, Han X, Fryer JD, Kowalewski T, Holtzman DM: ABCA1 is required for normal central nervous system ApoE levels and for lipidation of astrocyte-secreted apoE. J Biol Chem. 2004, 279: 40987-40993. 10.1074/jbc.M407963200. source
The Results section, “Plasma and CNS Apolipoprotein Levels in Abca1−/− Mice” (page unavailable), reports lower apoE protein levels in the cortex of mice with ABCA1 deletion. The paper compares deletion and partial deletion with wild-type mice; it does not report that ABCA1 overexpression decreases apoE levels. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [29] Hirsch-Reinshagen V, Zhou S, Burgess BL, Bernier L, McIsaac SA, Chan JY, Tansley GH, Cohn JS, Hayden MR, Wellington CL: Deficiency of ABCA1 impairs apolipoprotein E metabolism in brain. J Biol Chem. 2004, 279: 41197-41207. 10.1074/jbc.M407962200. source
- cites [30] Wahrle SE, Jiang H, Parsadanian M, Kim J, Li A, Knoten A, Jain S, Hirsch-Reinshagen V, Wellington CL, Bales KR, et al: Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease. J Clin Invest. 2008, 118: 671-682. source
The Introduction reports markedly lower brain apoE in mice lacking ABCA1. In “ApoE levels and solubility in PrP-mAbca1 Tg mice,” overexpression of sixfold or more reduced hippocampal apoE, but twofold overexpression did not alter it; the reduction also varied by brain region. The claim omits those limits on the overexpression finding. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Classified as probably not a substantial claim.
PremisecitationBrain levels of the cholesterol transporter ATP binding cassette A1 (ABCA1) alter the amount of apoE and the extent of apoE lipidation in mice.
“Brain levels of the cholesterol transporter ATP binding cassette A1 (ABCA1) also alter the amount of apoE and the extent of apoE lipidation in mice.”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [28] Wahrle SE, Jiang H, Parsadanian M, Legleiter J, Han X, Fryer JD, Kowalewski T, Holtzman DM: ABCA1 is required for normal central nervous system ApoE levels and for lipidation of astrocyte-secreted apoE. J Biol Chem. 2004, 279: 40987-40993. 10.1074/jbc.M407963200. source
- cites [29] Hirsch-Reinshagen V, Zhou S, Burgess BL, Bernier L, McIsaac SA, Chan JY, Tansley GH, Cohn JS, Hayden MR, Wellington CL: Deficiency of ABCA1 impairs apolipoprotein E metabolism in brain. J Biol Chem. 2004, 279: 41197-41207. 10.1074/jbc.M407962200. source
- cites [30] Wahrle SE, Jiang H, Parsadanian M, Kim J, Li A, Knoten A, Jain S, Hirsch-Reinshagen V, Wellington CL, Bales KR, et al: Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease. J Clin Invest. 2008, 118: 671-682. source
Classified as probably not a substantial claim.
PremisecitationIn transgenic mice that overexpress human amyloid precursor protein (APP), increasing ABCA1 levels causes a significant decrease in amyloid deposition in the brain.
“In transgenic mice that overexpress the human amyloid precursor protein (APP), increasing ABCA1 levels caused a significant decrease in amyloid deposition in the brain [30].”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [30] Wahrle SE, Jiang H, Parsadanian M, Kim J, Li A, Knoten A, Jain S, Hirsch-Reinshagen V, Wellington CL, Bales KR, et al: Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease. J Clin Invest. 2008, 118: 671-682. source
May combine two claims.
PremisecitationThe amyloid load in APP transgenic mice deficient in ABCA1 does not change, or even increases, when ABCA1−/− mice are crossed to various APP transgenic models.
“The amyloid load in APP transgenic mice deficient in ABCA1 did not change, or even increased, when ABCA1−/− mice were crossed to various APP transgenic models [40-42].”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [40] Hirsch-Reinshagen V, Maia LF, Burgess BL, Blain JF, Naus KE, McIsaac SA, Parkinson PF, Chan JY, Tansley GH, Hayden MR, et al: The absence of ABCA1 decreases soluble ApoE levels but does not diminish amyloid deposition in two murine models of Alzheimer disease. J Biol Chem. 2005, 280: 43243-43256. 10.1074/jbc.M508781200. source
- cites [41] Koldamova R, Staufenbiel M, Lefterov I: Lack of ABCA1 considerably decreases brain ApoE level and increases amyloid deposition in APP23 mice. J Biol Chem. 2005, 280: 43224-43235. 10.1074/jbc.M504513200. source
- cites [42] Wahrle SE, Jiang H, Parsadanian M, Hartman RE, Bales KR, Paul SM, Holtzman DM: Deletion of Abca1 increases Abeta deposition in the PDAPP transgenic mouse model of Alzheimer disease. J Biol Chem. 2005, 280: 43236-43242. 10.1074/jbc.M508780200. source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIncreasing the endocytosis of apoE via the low-density lipoprotein receptor (LDLR) decreases apoE levels in the mouse brain, likely through increased apoE clearance.
“Increasing the endocytosis of apoE via the low-density lipoprotein receptor (LDLR) has been shown to decrease apoE levels in the mouse brain, likely through increased apoE clearance [27].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [27] Kim J, Castellano JM, Jiang H, Basak JM, Parsadanian M, Pham V, Mason SM, Paul SM, Holtzman DM: Overexpression of low-density lipoprotein receptor in the brain markedly inhibits amyloid deposition and increases extracellular A beta clearance. Neuron. 2009, 64: 632-644. 10.1016/j.neuron.2009.11.013. source
Classified as probably not a substantial claim. May combine two claims.
PremisecitationPrevious studies have measured Aβ clearance from the brain either using 35S]methionine labeling or by measuring the disappearance of Aβ following the pharmacological inhibition of Aβ production.
“Previous studies have measured Aβ clearance from the brain either using 35 S]methionine labeling [48], or by measuring the disappearance of Aβ following the pharmacological inhibition of Aβ production [49-51].”
Quote in the paperSubstantial claim2 of 4 sources checked- cites [48] Savage MJ, Trusko SP, Howland DS, Pinsker LR, Mistretta S, Reaume AG, Greenberg BD, Siman R, Scott RW: Turnover of amyloid beta-protein in mouse brain and acute reduction of its level by phorbol ester. J Neurosci. 1998, 18: 1743-1752. source
- cites [49] Cirrito JR, May PC, O’Dell MA, Taylor JW, Parsadanian M, Cramer JW, Audia JE, Nissen JS, Bales KR, Paul SM, et al: In vivo assessment of brain interstitial fluid with microdialysis reveals plaque-associated changes in amyloid-beta metabolism and half-life. J Neurosci. 2003, 23: 8844-8853. source
- cites [50] Barten DM, Guss VL, Corsa JA, Loo A, Hansel SB, Zheng M, Munoz B, Srinivasan K, Wang B, Robertson BJ, et al: Dynamics of {beta}-amyloid reductions in brain, cerebrospinal fluid, and plasma of {beta}-amyloid precursor protein transgenic mice treated with a {gamma}-secretase inhibitor. J Pharmacol Exp Ther. 2005, 312: 635-643. source
- cites [51] Abramowski D, Wiederhold KH, Furrer U, Jaton AL, Neuenschwander A, Runser MJ, Danner S, Reichwald J, Ammaturo D, Staab D, et al: Dynamics of Abeta turnover and deposition in different beta-amyloid precursor protein transgenic mouse models following gamma-secretase inhibition. J Pharmacol Exp Ther. 2008, 327: 411-424. 10.1124/jpet.108.140327. source
May combine two claims.
PremisecitationAt metabolic steady state, the fraction of the pool that is synthesized per unit time equals the fraction of the pool catabolized per unit time (FCR), which can be calculated as the negative of the slope of the natural log of TTR plotted over time.
“At metabolic steady state, the fraction of the pool that is synthesized per unit time equals the fraction of the pool catabolized per unit time (FCR), which can be calculated as the negative of the slope of the natural log of TTR plotted over time [53].”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [53] Patterson BW, Mittendorfer B, Elias N, Satyanarayana R, Klein S: Use of stable isotopically labeled tracers to measure very low density lipoprotein-triglyceride turnover. J Lipid Res. 2002, 43: 223-233. source
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured
The quote only partly states this claim.
Findingown dataABCA1 levels (overexpression or deletion) do not alter the pool size of Aβ in the mouse brain.
“For Aβ, no differences were observed in the FCR, PS, or PR values (Table 3).”
Quote in the paperSubstantial claim- Rests on an assumption: The disappearance of 13C6-leucine-labeled apoE and Aβ from the brain follows a monoexponential decay, so the negative slope of the log-transformed labeled/unlabeled ratio over time equals the fractional clearance rate.
- Rests on an assumption: The immunoprecipitation and MRM assays measure only the intended apoE and Aβ peptides, without interference from other proteins or peptides.
- Rests on an assumption: The FCR of total Aβ reflects the clearance of the relevant Aβ species in the brain.
May combine two claims.
Findingown dataThe apoE FCR is 1.9-fold faster in ABCA1−/− mice compared to wild-type mice, and this difference is statistically significant.
“The apoE FCR was 1.5-fold faster in ABCA1 Tg mice and 1.9-fold faster in ABCA1−/− mice compared to Wt mice; however the difference was only significant for the ABCA1−/− mice.”
Quote in the paperSubstantial claim- Rests on an assumption: The disappearance of 13C6-leucine-labeled apoE and Aβ from the brain follows a monoexponential decay, so the negative slope of the log-transformed labeled/unlabeled ratio over time equals the fractional clearance rate.
- Rests on an assumption: The immunoprecipitation and MRM assays measure only the intended apoE and Aβ peptides, without interference from other proteins or peptides.
May combine two claims.
Findingown dataThe apoE FCR is 1.5-fold faster in ABCA1 transgenic mice compared to wild-type mice, but the difference is not statistically significant.
“The apoE FCR was 1.5-fold faster in ABCA1 Tg mice and 1.9-fold faster in ABCA1−/− mice compared to Wt mice; however the difference was only significant for the ABCA1−/− mice.”
Quote in the paperNot a substantial claim- Rests on an assumption: The disappearance of 13C6-leucine-labeled apoE and Aβ from the brain follows a monoexponential decay, so the negative slope of the log-transformed labeled/unlabeled ratio over time equals the fractional clearance rate.
- Rests on an assumption: The immunoprecipitation and MRM assays measure only the intended apoE and Aβ peptides, without interference from other proteins or peptides.
May combine two claims.
Findingown dataABCA1 overexpression and deletion have no effect on the Aβ fractional clearance rate, and at a young age prior to plaque deposition ABCA1 levels do not alter Aβ clearance from the mouse brain.
“but have no effect on the Aβ fractional clearance rate.”
- Also stated in: § Effect of ABCA1 levels on apoE and Aβ clearance rates · hedged
“our results suggest that at a young age prior to the onset of plaque deposition, ABCA1 levels do not alter Aβ clearance from the mouse brain.”
- Also stated in: § Conclusions · plain
“Increasing ABCA1 or deleting ABCA1 from the brain had no effect on Aβ clearance.”
Quote in the paperSubstantial claim- Rests on an assumption: The mice used in the Aβ clearance experiments were at a young age prior to the onset of plaque deposition.
- Rests on an assumption: The antibodies used for immunoprecipitation and ELISA specifically and quantitatively measure apoE and Aβ.
- Also stated in: § Effect of ABCA1 levels on apoE and Aβ clearance rates · hedged
May combine two claims.
Interpretationown dataApoE clearance is enhanced in the brains of LDLR transgenic mice, providing the likely explanation for the decreased total apoE protein levels.
“These results convincingly demonstrate that apoE clearance is enhanced in the brains of LDLR Tg mice, providing the likely explanation for the decreased total apoE protein levels.”
Quote in the paperSubstantial claim- Rests on an assumption: The disappearance of 13C6-leucine-labeled apoE and Aβ from the brain follows a monoexponential decay, so the negative slope of the log-transformed labeled/unlabeled ratio over time equals the fractional clearance rate.
- Rests on an assumption: The immunoprecipitation and MRM assays measure only the intended apoE and Aβ peptides, without interference from other proteins or peptides.
May combine two claims.
Study design and conductown dataThe measured amount of percent labeled apoE gave values very close to expected values, with a linear fit slope of 0.976 and an R2 value of 0.9954.
“The measured amount of percent labeled apoE gave values that were very close to the expected values (Figure 2C). The linear fit had a slope of 0.976 and an R2 value of 0.9954.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationDifferent mouse strains can have up to a four-fold difference in plasma apoE levels.
“Studies have shown that different mouse strains can have up to a four-fold difference in plasma apoE levels [36,37].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [36] Lusis AJ, Taylor BA, Quon D, Zollman S, LeBoeuf RC: Genetic factors controlling structure and expression of apolipoproteins B and E in mice. J Biol Chem. 1987, 262: 7594-7604. source
- cites [37] Srivastava RA, Krul ES, Lin RC, Schonfeld G: Regulation of lipoprotein metabolism by estrogen in inbred strains of mice occurs primarily by posttranscriptional mechanisms. Mol Cell Biochem. 1997, 173: 161-168. 10.1023/A:1006896131186. source
May combine two claims.
Interpretationown dataThe pulsed 13C6-leucine injection labeling technique is effective for measuring the clearance of proteins from the brain and can detect differences in FCRs between genetically modified mouse models.
“We therefore concluded that the pulsed 13 C6-leucine injection labeling technique is effective for measuring the clearance of proteins from the brain, and could be used to detect differences in FCRs between genetically modified mouse models.”
Quote in the paperSubstantial claim- Rests on an assumption: The disappearance of 13C6-leucine-labeled apoE and Aβ from the brain follows a monoexponential decay, so the negative slope of the log-transformed labeled/unlabeled ratio over time equals the fractional clearance rate.
- Rests on an assumption: The immunoprecipitation and MRM assays measure only the intended apoE and Aβ peptides, without interference from other proteins or peptides.
Classified as probably not a substantial claim.
Study design and conductreasoningAll experiments were performed on young animals (3.5 months old) prior to the onset of detectable plaque deposition to limit complications due to Aβ extraction from tissue with amyloid plaques.
“To limit complications due to Aβ extraction from tissue with amyloid plaques, all experiments were performed on young animals (3.5 months old) prior to the onset of detectable plaque deposition.”
Quote in the paperSubstantial claim- Rests on an assumption: The 3.5-month-old APP transgenic mice have no detectable amyloid plaques that would complicate Aβ extraction.
May combine two claims.
PremisecitationPlasma kinetic studies in humans with loss-of-function mutations in ABCA1 demonstrated increased catabolism of HDL and LDL B-100, suggesting decreased stability of poorly lipidated lipoprotein particles.
“These studies demonstrated that the catabolism of both high-density lipoprotein (HDL) and low-density lipoprotein apolipoprotein B-100 (LDL B-100) were increased in the plasma of these individuals [44,45], suggesting decreased stability of poorly lipidated lipoprotein particles.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [44] Schaefer EJ, Anderson DW, Zech LA, Lindgren FT, Bronzert TB, Rubalcaba EA, Brewer HB: Metabolism of high density lipoprotein subfractions and constituents in Tangier disease following the infusion of high density lipoproteins. J Lipid Res. 1981, 22: 217-228. source
- cites [45] Schaefer EJ, Brousseau ME, Diffenderfer MR, Cohn JS, Welty FK, O’Connor J: Dolnikowski GG, Wang J, Hegele RA, Jones PJ: Cholesterol and apolipoprotein B metabolism in Tangier disease. Atherosclerosis. 2001, 159: 231-236. 10.1016/S0021-9150(01)00688-8. source
May combine two claims.
Premisecitation13C6-labeled leucine is an essential amino acid that rapidly crosses the blood-brain barrier via facilitative neutral amino acid transport.
“We chose 13 C6-labeled leucine because it is one of the essential amino acids that rapidly crosses the blood brain barrier via facilitative neutral amino acid transport [34].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [34] Smith QR, Momma S, Aoyagi M, Rapoport SI: Kinetics of neutral amino acid transport across the blood–brain barrier. J Neurochem. 1987, 49: 1651-1658. 10.1111/j.1471-4159.1987.tb01039.x. source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationLDLR is a receptor that binds to apolipoprotein B and apoE in the periphery to facilitate the uptake of cholesterol-laden lipoproteins by cells.
“LDLR is a receptor that binds to apolipoprotein B and apoE in the periphery to facilitate the uptake of cholesterol-laden lipoproteins by cells [38].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [38] Brown MS, Goldstein JL: A receptor-mediated pathway for cholesterol homeostasis. Science. 1986, 232: 34-47. 10.1126/science.3513311. source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
InterpretationreasoningThough both ABCA1 overexpression and deletion led to enhanced apoE clearance, the mechanism underlying the difference in each case may be different.
“Therefore, though both ABCA1 overexpression and deletion led to enhanced apoE clearance, the mechanism underlying the difference in each case may be different.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAll experimental protocols were approved by the Animal Studies Committee at Washington University in St. Louis.
“All experimental protocols were approved by the Animal Studies Committee at Washington University in St. Louis.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningOur technique has unique advantages in that it does not require a radioactive tracer and kinetics are determined in the steady-state, which does not occur with the inhibition of Aβ production.
“In comparison to other studies, our technique has unique advantages in that it does not require a radioactive tracer and kinetics are determined in the steady-state, which does not occur with the inhibition of Aβ production.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Interpretationnone givenThe SILK technique can be applied in any laboratory setting that has access to MS instrumentation.
“The SILK technique is not particularly expensive and can be applied in any laboratory setting that has access to MS instrumentation.”
Quote in the paperNot a substantial claimMay combine two claims.
Study design and conductown dataThe mice were in steady-state conditions, since the amount of apoE and Aβ did not significantly change over the time period of the kinetic analysis.
“The mice were in steady-state conditions, since the amount of apoE and Aβ did not significantly change over the time period of the kinetic analysis.”
Quote in the paperSubstantial claim- Rests on an assumption: The antibodies used for immunoprecipitation and ELISA specifically and quantitatively measure apoE and Aβ.
The paper relies on this without support.
The disappearance of 13C6-leucine-labeled apoE and Aβ from the brain follows a monoexponential decay, so the negative slope of the log-transformed labeled/unlabeled ratio over time equals the fractional clearance rate.
“The negative of the slope of the monoexponential curve was then calculated in order to determine the fractional clearance rate for each protein from the brain.”
The paper relies on this without support.
The immunoprecipitation and MRM assays measure only the intended apoE and Aβ peptides, without interference from other proteins or peptides.
“Multiple reaction monitoring (MRM) assays were developed for each protein by first selecting a peptide that shows high MS signal intensity, contains only one leucine residue, and is specific for each protein (LQAEIFQAR for apoE, LVFFAEDVGSNK for Aβ).”
The paper relies on this without support.
The 3.5-month-old APP transgenic mice have no detectable amyloid plaques that would complicate Aβ extraction.
“To limit complications due to Aβ extraction from tissue with amyloid plaques, all experiments were performed on young animals (3.5 months old) prior to the onset of detectable plaque deposition.”
The paper relies on this without support.
The FCR of total Aβ reflects the clearance of the relevant Aβ species in the brain.
“Total Aβ was immunoprecipitated from the cortex and the labeled/unlabeled ratios were then plotted versus time for each genotype.”
The paper relies on this without support.
The standard curve generated from astrocyte-secreted apoE is representative of brain apoE labeling.
“Since astrocytes are the main cell type in the brain that produce apoE [20], we used primary astrocyte cultures to produce a labeled apoE standard curve.”
The paper relies on this without support.
The mice used in the Aβ clearance experiments were at a young age prior to the onset of plaque deposition.
“at a young age prior to the onset of plaque deposition”
The paper relies on this without support.
The antibodies used for immunoprecipitation and ELISA specifically and quantitatively measure apoE and Aβ.
“HJ5.2 (Aβ) and HJ6.3 (ApoE) antibodies were made in-house.”
“Protein concentrations of apoE and Aβ in the lysates were determined by protein-specific sandwich ELISAs using in-house antibodies.”
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“Previously we have shown that LDLR transgenic mice that overexpress LDLR in the brain have significantly decreased levels of brain apoE [27].”
BackgroundMethodInfluentialSelf-citationHirsch-Reinshagen, V., Maia, L. F., Burgess, B. L., Blain, J.-F., Naus, K. E., McIsaac, S. A., Parkinson, P. F., Chan, J. Y., Tansley, G. H., Hayden, M. R., et al. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m508781200 · Cited by 233 · see citing works
Turnover of Amyloid β-Protein in Mouse Brain and Acute Reduction of Its Level by Phorbol Ester
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Kim, J., Jiang, H., Park, S., Eltorai, A. E. M., Stewart, F. R., Yoon, H., Basak, J. M., Finn, M. B., & Holtzman, D. M. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.3773-11.2011 · Cited by 199 · cited 1× · see citing works
“Independent of apoE isoform, the amount of apoE in the brain appears to be critical for determining the extent of amyloid deposition [25,26].”
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Genetic factors controlling structure and expression of apolipoproteins B and E in mice.
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Measurement of tissue protein synthesis rates in vivo: a critical analysis of contrasting methods
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Measurement of muscle protein fractional synthesis and breakdown rates from a pulse tracer injection
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Update on the Neuropathological Diagnosis of Frontotemporal Dementias
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Protein turnover on the scale of the proteome
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Enhanced synthesis of albumin and fibrinogen at high altitude
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Cholesterol and apolipoprotein B metabolism in Tangier disease
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“These studies demonstrated that the catabolism of both high-density lipoprotein (HDL) and low-density lipoprotein apolipoprotein B-100 (LDL B-100) were increased in the plasma of these individuals [44,45], suggesting decreased stability of poorly lipidated lipoprotein particles.”
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Neurofilaments: neurobiological foundations for biomarker applications
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Analysis of in vivo turnover of tau in a mouse model of tauopathy
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Self-citationActivation of PPARα enhances astroglial uptake and degradation of β-amyloid
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SILK studies — capturing the turnover of proteins linked to neurodegenerative diseases
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Self-citationConcerning the structure of apoE
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Can insulin signaling pathways be targeted to transport Aβ out of the brain?
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Apo<scp>E</scp>: The role of conserved residues in defining function
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Is liquid biopsy mature enough for the diagnosis of Alzheimer’s disease?
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Mass Spectrometry‐Based Analysis of Time‐Resolved Proteome Quantification
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Advances in Alzheimer’s disease: mechanistic insights and therapeutic targets
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Long-lived proteins and DNA as candidate predictive biomarkers for tissue associated diseases
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Small Molecule Phenotypic Screen Identifies Novel Regulators of LDLR Expression
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Alzheimer’s Disease Therapeutics Targeting Apolipoprotein E
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Self-citationQuantifying protein kinetics in vivo: influence of precursor dynamics on product labeling
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Brain shuttle peptides: From permeability assay toolbox to data-driven discovery
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- Authors
- Basak, J. M., Kim, J., Pyatkivskyy, Y., Wildsmith, K. R., Jiang, H., Parsadanian, M., Patterson, B. W., Bateman, R. J., & Holtzman, D. M.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Holtzman, David M
- Venue
- Molecular Neurodegeneration
- Published
- 2012-04-18
- Volume
- 7
- Issue
- 1
- Pages
- 14-14
- ISSN
- 1750-1326 (ISSN-L)
- PMC
- PMC3405485
- OpenAlex
- W2138786214
- Semantic Scholar
- a8188b1b9fa0539ab5567918f0fe0ca4a7c67ac2
- Cited by
- 27
- References
- 54
- Citations by year
- 2026: 2 · 2024: 3 · 2022: 2 · 2021: 2 · 2020: 4 · 2019: 2 · 2016: 2 · 2015: 4 · 2014: 1 · 2013: 4 · 2012: 1
- FWCI
- 1.89
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Molecular Neurodegeneration (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- Europe PMC (PubMed Central) (submittedVersion, cc-by)
- PubMed Central (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- American Health Assistance Foundation
- Eli Lilly and Company
- National Institutes of Health (5p30ns069329-02, P50 AG005681, P30DK056341, AG13956, NS057105)
- National Institute on Aging (P50‐AG005681, K23 AG 03094601, R01 AG013956, AG13956, K23AG030946)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30-DK056341)
- National Institute of Neurological Disorders and Stroke (NS06566704, P30-NS069329, NS034467, P30 NS057105)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Physical Sciences › Chemistry › Spectroscopy › Mass Spectrometry Techniques and Applications
- Keywords
- apolipoprotein E, amyloid-beta, fractional clearance rate, ABCA1, LDL receptor, Alzheimer's disease, neurodegenerative diseases, protein turnover
- MeSH terms
- Animals, Apolipoproteins E, Brain, Carbon Isotopes, Chromatography, Liquid, Isotope Labeling, Mice, Inbred C57BL, Mice, Transgenic, Radioactive Tracers, Mass Spectrometry, Amyloid beta-Peptides, Immunoprecipitation, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-17.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-17.
Cited sources are checked by gpt-6-sol.
Statistics and arithmetic are recomputed, not judged.
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